Studies have shown CXCL12 (also called stromal cell-derived factor-1 or SDF-1) and CXCR4, a chemokine and chemokine receptor pair play important roles in hematopoiesis, multiple stages of tumorigenesis, and embryonic development (Broxmeyer, H. E. et al., Int. J. Hematol. 2001, 74, 9-17; Horuk, R., Nat. Rev. Drug Discov. 2009, 8, 23-33). For example, activation of CXCR4 by CXCL12 has shown to direct leukocyte chemotaxis in the immune system in response to inflammation and progenitor cell migration during embryologic development. Activation of CXCR4 by CXCL12 has also been shown to mediate signaling pathway that is involved in breast cancer metastasis and memory T cell migration (Orimo, A., et al., Cell 2005, 121, 335-348).
CXCR4, a G-protein-coupled receptor also known as fusin or CD184 (cluster of differentiation 184), is constitutively- or over-expressed in a wide variety of human cancers, promoting local tumor cell proliferation, survival and angiogenesis (Huang, E. H., et al., J. Surg. Res. 2009, 155, 231-236). It has also been reported that CXCR4 is a co-receptor for HIV entry and infection of host cells and has been evaluated as a potential HIV therapy (Tamamura, H., et al., Biochem. Biophys. Res. Commun. 1998, 253, 877-882; Oberlin, E. et al., Nature, 1996, 382, 833-835).
Reports have confirmed that CXCR4 is overexpressed in numerous human cancers. CXCR4 antagonism has been shown to disrupt tumor-stromal interactions, sensitize cancer cells to cytotoxic drugs, and reduce tumor growth and metastatic burden. Hence, CXCR4 is a target not only for potential therapeutic intervention of cancer treatment, but also for noninvasive monitoring of disease progression, therapeutic guidance, and other diagnostic purposes (Chatterjee, S. et al., Adv Cancer Res. 2014; 124:31-82). Binding and Interacting with CXCR4 have been suggested as a potential way of targeted drug delivery (Wang, Y. et al., Curr Pharmcol Rep (2016) 2:1-10).
Thus, it is believed that compounds having a moiety that can selectively bind CXCR4 (i.e., CXCR4 selective binding conjugate) can have a wide variety uses including, but not limited to, in treating a wide array of clinical conditions associated with activation or over-expression of CXCR4, diagnosing a patient, and in mediacl imaging.
Accordingly, there is a need for conjugates that can selectively bind to CXCR4.